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Abstract: FR-PO247

High-Fat Feeding in Pkd1 RC/RC Mice Associates With Upregulation of Havcr1 and Immune Activation

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Iliuta, Ioan-Andrei, University Health Network, Toronto, Ontario, Canada
  • Song, Xuewen, University of Toronto Temerty Faculty of Medicine, Toronto, Ontario, Canada
  • Haghighi, Amirreza, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • He, Ning, University of Toronto Temerty Faculty of Medicine, Toronto, Ontario, Canada
  • Nasri, Fatemeh, University Health Network, Toronto, Ontario, Canada
  • Scholey, James W., University Health Network, Toronto, Ontario, Canada
  • Pei, York P., University Health Network, Toronto, Ontario, Canada

Autosomal dominant polycystic kidney disease (APDKD) is the most common inherited nephropathy worldwide and an important cause of end-stage renal disease. The effects of overweight on ADPKD are unclear, although recent clinical research suggests increased body mass index might be an independent risk factor for disease severity. In addition, high-fat feeding aggravated cystic disease in two orthologous mouse models of ADPKD, possibly in association with impaired fatty acid oxidation in the cystic epithelium. We explored the effects of a high-fat diet (HFD) in young Pkd1 RC/RC mice, a hypomorphic model of ADPKD characterized by slow progression of cystic disease similarly to human ADPKD.


Since Pkd1 RC/RC mice exhibit sexual dimorphism, with females showing more severe cystic disease, we assigned 20 females and 20 males in a 1:1 ratio to either a HFD, with 60% of calories derived from fat, or a carbohydrate-rich “normal diet” (ND), with 10% of calories derived from fat. Mice were started on the diets at 2 months of age and sacrificed at 7 months of age. We then assessed kidney weight and volume, histology and histomorphometry, biochemistry, and gene expression. In addition to microarray analysis, we performed gene-set enrichment using Enrichr.


HFD compared to ND feeding associated with increased kidney volume (p<0.0001) and cystic index (p=0.001) in females, but it did not associate with reduced kidney function. In the kidneys of females fed a HFD compared to a ND, we identified: (1) upregulation of Havcr1 (FDR p=0.0009), a pro-inflammatory biomarker of renal tubular injury; (2) enrichment in pathways involved in innate and adaptive immunity, with a majority of these genes upregulated in our dataset; (3) enrichment in EP300 (adjusted p=8.7*10-21), a transcriptional co-activator of cell proliferation, which was upregulated in our dataset; (4) enrichment in PPARα (adjusted p=8.5*10-10), a major regulator of fatty acid oxidation, which was downregulated in our dataset; and (5) evidence of macrophage accumulation on immunohistochemistry (p=0.07).


HFD feeding in female Pkd1 RC/RC mice aggravated the kidney cyst burden, in association with a transcriptomic profile suggesting early-stage inflammatory kidney injury and inhibited fatty acid oxidation.


  • Government Support – Non-U.S.